In initial studies of LRRK2 signaling function in macrophages/dendritic cells we established that cells from mice bearing an LRRK2 transgene manifest increased cytokine responses when exposed to innate ligands that stimulate cells by activating SYK, a cell surface signaling molecule involved in dectin receptor signaling and to a lesser extent in TLR signaling. This, plus the fact that in Western blot studies we determined that LRRK2 interacts with SYK as well as with components of the downstream SYK-associated signaling complex, BCL10/MALT-1/CARD9 provided important support for the idea that LRRK2 acts as component of the SYK signaling pathway. In studies more specifically addressing how LRRK2 affects autophagy we found, somewhat to our surprise, that macrophages from LRRK2 transgenic mice upon stimulation of the dectin pathway exhibit decreased conversion of LC3 to LC3 II, the latter a molecule that appears at the distal end of the activated autophagy pathway. Complementary studies of macrophages from LRRK2-deficient mice showed that LRRK2 deficiency was associated with increased autophagy, thus confirming the result obtained with transgenic cells. In additional studies to address the issue of the molecular mechanism of LRRK2-mediated autophagy inhibition we showed that LRRK2 interacts with the autophagy initiator, beclin, and such interaction is associatd with breakdown of beclin dimers. Beclin breakdown may be mediated by caspase8 since LRRK2 also interacts with caspase8 and the latter is component of the BCL10 signaling complex mentioned above. Recent studies from other laboratories have shown that autophaphy leads to inhibition of activation and also to disturbances in IL-1beta signaling. The present studies therefore suggest that one of the mechanisms by which LRRK2 polymorphisms contribute to the inflammation of Crohn's disease is that these polymorphisms result in autophagy-related defects in the normal regulation of pro-inflammatory inflammasome/IL-1beta secretiion.